Protein kinase C (PKC) is a ubiquitous enzyme system which plays an impressive role in a host of signal transduction processes. The teleocidins, lyngbyatoxins, and olivoretins represent a large family of alkaloids which like the phorbol esters act as powerful tumor promoting agents. These compounds bind to the diacylglycerol (DAG) binding site of protein kinase C and potently activate the enzyme system. Since PKC has been shown to represent the predominant phosphorylation system in leukemic cells, potent inhibitors of the enzyme may provide new agents for cancer therapy. Inhibitors of PKC might also become useful drug candidates for treating other disease states including inflammatory disorders, psoriasis, and asthma. Accordingly, it is our aim to discover "diacylglycerol site-specific" inhibitors of PKC through chemical modification of the lyngbyatoxin structure. The new compounds synthesized will be studied for their biological effects in selected PKC assay systems. Potent DAG-site specific inhibitors of PKC should accordingly find immediate use as pharmacological research tools for the investigation of signal transduction processes and serve as new leads in the discovery of agents for the treatment of a variety of clinical disorders.